Physical exercise is a critical regulator of numerous growth and metabolic processes in skeletal muscle. For example, exercise can significantly alter the rates of glucose uptake, glycogen metabolism, protein synthesis, and gene transcription in the working muscle. The long term goal of this project is to elucidate the underlying molecular signaling mechanisms through which physical exercise regulates these growth and metabolic processes in skeletal muscle. The immediate goal of the experiments proposed in this application is to determine the biological consequences of exercise-induced activation of the mitogen-activated protein kinase (MAP kinase) signaling cascades. The first specific aim is to determine the isoform-specific pattern of p38 activity with muscle contraction and to determine if p38 signaling functions to regulate glucose uptake in contracting skeletal muscle. Specific aim 2 is designed to elucidate the effects of c-jun kinase (JNK) ablation on systemic responses to exercise, and to determine how alterations in JNK signaling affect the ability of exercise to regulate glycogen metabolism, glucose uptake, and intracellular signaling proteins in skeletal muscle. Specific aim 3 will test the hypothesis that activated MAP kinase signaling regulates changes in gene expression following exercise. In addition to these aims, other novel signal pathways and molecules will be investigated that may eventually prove to be critical in regulating the numerous biological effects of exercise in skeletal muscle. These studies will continue to define the molecular mechanisms of exercise-stimulated changes in skeletal muscle growth and metabolism. Ultimately, these studies should provide us with a better understanding of how regular physical exercise exerts salutary effects on several human diseases.